Tumor Angiogenesis-targeted Nano Gold Probes For Lung Cancer Diagnosis And Therapy

As the early symptoms are not obvious and hard to diagnose at early stage,lung cancer,is one of cancers with the first incidence and mortality in our country and world wide.Nearly 70 % of confirmed patients are already at advanced stage,or even with widespread systemic metastases.Therefore,five-year survival rate of lung cancer patients is extremely low.Especially in our country,five-year survival rate of lung cancer patients is nearly less than 10%.However,lung cancer patients were early diagnosed and received therapic treatment,five-year survival rate of them can reach to more than 80%.The therapic treatment of cancer is mainly about chemotherapy,radiotherapy,surgery and multi-models combined therapy.As the radiotherapy was limited by tolerance radiation dose of normal tissues,radiosensitiztion therapy is considered as an ideal strategy for lung cancer treatment.In this regard,find a new multifunctional platform for lung cancer early diagnosis and therapy,especially for radiotherapy effect improvement,is highly desired.In recent years,with the rapid development of nanotechnology,metal nanomaterials as a new diagnostic reagent,contrast agent,radiosensitize agent and anticancer drug carrier,are widely used in theranostics of tumors.Among these metal nanomaterials,gold nanomaterial,owing to its advantageous features like various structures,large energy absorption coefficient,ease to modification and good biocompatibility,are emerging as one of most promising agent for drug delivery,diagnostic and therapy.In addition,due to their high Z number and thus high efficiency in generating photoelectrons and Auger electrons under ?-ray or X-ray irradiation,gold nanomaterial has also been demonstrated an effective radiosensitizer.Therefore,gold nanomaterial is considered as an ideal platform for cancer chemoradiotherapy.However,concentration of probes in the tumor region has been a key factor affecting the accurate diagnosis and treatment efficiency of tumors.Therefore,selecting an effective targeting receptor enables the probe to specifically target to tumor region and achieve high accumulation efficiency in tumor is significant.Targeting tumor angiogenesis by the probes not only enables the early diagnosis of tumors,but also allow the tumors angiogenesis received an administering reasonable dose of therapic treatment.Those treatments may damage the tumor neovascularization directly,cut off oxygen and nutrient supply for tumor growth and metastasis,acheving to more effective tumor therapic treatment.Clinical treatment of lung cancer is mainly based on radiotherapy and chemotherapy.However,there are some urgent problems need to be solved for utilization of gold nano materials for tumor diagnosis and therapy:(1)For radiosensitization,high accumulation efficiency in tumor region of the probes may achieve a better effective of tumor radiosensitization therapy.However,we still don't know which kind of probes with a typical morphology and size are the most suitable one for radiosensitization therapy.We also should know the optimal time point at which the particle accumulation within the tumor is maximal and expect to significantly influence the measured outcome.(2)Chemoradiotherapy is usually more effective than chemotherapy or radiotherapy alone.However,the evaluation of the synergistic therapic efficiency of angiogenesis-targeted probes for chemoradiotherapy is seldom reported.Due to the accumulation efficiency of probes may affect the tumor synergistic therapic effect,we need to know the suitable morphology of probes with high tumor accumulation efficiency and keep on exploring the property of probes in tumor sub-organ kinetics.(3)Due to photothermal therapy owing to the properties of small invasive,therapic effective obviously,it is a novel tumor therapic treatment and has called great attention recently.However,photothermal therapy has some nonnegligible shortcomings,such as less-than-ideal soft tissue penetration,leading to insufficient tumor cell killing and failure to prevent tumor recurrence by initial treatment.So,it is highly desired to design a tumor specifically targeted probes with the abilities of tumor early diagnosis and high photo-thermal conversion efficiency.By loading anti-cancer drug,the probes can be an ideal platform for chemo-thermal therapy,to ablate the tumor sufficiently and prevent the tumor recurrence.In this study,tumor angiogenesis-targeted,cisplatin-loaded,and radioisotope iodine-125 labeled gold nanoparticle(GNP)and gold nanorod(GNR)probes were developed.We explored influence of size and morphology of probes to tumor accumulation efficiency,and we also developed a mathematical model to describe the suborgan kinetics of GNPs and GNRs probes.By loading chemotherapeutic drug cisplatin,the target probes exhibited both high radiotherapy efficiency,chemo-radiotherapy and chemo-photothermal combined therapy efficiency,leading to a sufficient tumor ablation.The main work of this paper includes the following aspects:1.Synthesis different sizes of gold nanospheres and gold nanorods.Characterize the size,morphology,optical properties of gold nanospheres and gold nanorods.2.we developed cyclic c(RGDyC)-peptide(abbreviated RGD)-conjugated,Gd-and 99 mTc-labeled AuNPs probes(RGD@AuNPs-Gd99 mTc)to enable specific localization to tumors of AuNPs that could be simultaneously monitored with both MRI and nuclear imaging methodologies.Further,we produced three different sizes(particles with a diameter of 29,51,or 80 nm)and evaluated their effectiveness as radiosensitizers both in vitro and in vivo.We found that all three probes exhibit high specificity for ?v?3 integrin positive cells and tumor angiogenic vessels.The 80 nm RGD@AuNPs-Gd99 mTc was internalized by tumor cells most efficiently and thus exhibited the greatest degree of radiosensitization in vitro.However,in vivo,the 29 nm RGD@AuNPs-Gd99 mTc exhibited greater tumor accumulation and thus were ultimately found to be most effective for tumor radiosensitization therapy.3.We established cyclic c(RGDyC)-peptide conjugated,cisplatinloaded,and radioisotope iodine-125 labeling tumor angiogenesis-targeted gold nanoparticles(GNPs)and gold nanorods(GNRs)platforms.A parallel study on accumulation of tumor tissues was performed by SPECT and photoacoustic imaging,and the performances of chemo-radiation synergetic therapy of tumor were evaluated both in vitro and in vivo.We found that both GNPs and GNRs probes exhibit high specificity to ?v?3 integrin positive cells and tumor angiogenic vessels.The GNRs probes were internalized more efficient than GNPs probes by tumor cells in vitro,they were also exhibited greater tumor accumulation and chemo-radiation synergetic therapy efficiency in vivo.To furtherly explain those results,a mathematical model was developed to describe the suborgan kinetics of GNPs and GNRs probes,and furtherly speculated the influence factors of their accumulation in tumor tissues.4.We developed a chemo-photothermal theranostic platform based on polydopamine(PDA)-coated gold nanorods(GNRs).The PDA coating was thin;however,it significantly suppressed the cytotoxicity of the cetyltrimethylammonium bromide template and allowed high cisplatin loading efficiency,arginine-glycine-aspartic acid(RGD)peptide(c(RGDyC))conjugation,and chelator-free iodine-125 labeling(RGD-125IPt-PDA@GNRs).While loaded cisplatin was released in a pH-sensitive manner,labeled 125 I was outstandingly stable under biological conditions.RGD-125IPt-PDA@GNRs had a high specificity for ?v?3 integrin,and consequently,they could selectively accumulate in tumors,as revealed by single photon emission computed tomography/CT imaging,and in target tumor angiogenic vessels,as shown by high-resolution photoacoustic imaging.As RGD-125IPt-PDA@GNRs targets tumor angiogenesis,it is a highly potent tumor therapy.Combined chemo-photothermal therapy with probes could thoroughly ablate tumors and inhibit tumor relapse via a synergistic antitumor effect.Our studies demonstrated that RGD-125IPtPDA@GNRs is a robust platform for image-guided,chemo-thermal tumor therapy with outstanding synergistic tumor killing and relapse inhibition effects.